You need to get calories from somewhere, should it be from carbohydrate or fat?

Monday, December 07, 2015

Protons (42) Metformin as the next epilepsy drug?

Some things which are written in stone are not quite as they seem. In a chat to karl about metformin/lactate in the brain I started thinking about the control of glucose derived calories being delivered to neurons. There is a general understanding that the brain does not use insulin signalling to control glucose entry to neurons, just as it doesn’t oxidise fatty acids. However we know that astrocytes certainly oxidise fatty acids to ketones and feed those ketones to the neurons, so the old chestnut about the "brain" not oxidising fatty acids is rather limited in its application. Does the same apply to glycolysis and glucose ingress? What about glial cells and insulin signalling?

It’s a beautiful example of massively clever people who never ask the correct question. I opened the full text and slogged through reams and reams of alphabet soup about insulin signalling in astrocytes. The group are probably planning on maintaining funding by linking modifications of this "alphabet soup" to the development of type 3 diabetes, Alzheimer’s Disease. Great plan.

Of course personally I’m looking for changes in glucose metabolism related to insulin signalling. There is a sh!t load of mtG3Pdh in the mitochondria extracted from homogenised brain tissue and clearly it's doing something there. And that something, as far as I’m concerned, is related to linking glucose ingress to insulin signalling. The initiation and curtailing of insulin signalling in relationship to glucose flux.

After some time spent in the mire of alphabet soup I eventually searched the paper using “glucose” to see if I was missing some deep insight amidst the said alphabet soup.

No. glucose is only mentioned twice. The in-text the mention is irrelevant (talking about hepatic-like cell insulin resistance under fructose). The second mention is in a reference. This is a gem. Back in 1984 we knew this:

I would expect high levels of mtG3Pdh to be associated with very tight regulation of the glucose metabolism mediated through insulin signalling. Not in neurons. Neurons should use lactate. Glycolysis, especially the side-spur to the glycerophosphate shuttle, should be a pathway of last resort for neurons.

Not so in astrocytes. They should really, really tightly control the flux of glucose through themselves as they are the guardians of the neurons. They should meter insulin signalling to control lactate generation for supply to neurons.

Trying to link insulin signalling to Alzheimer’s Disease, without looking at glucose metabolism, leaves you wallowing in an alphabet soup with no way of generating a plan other than to develop some drug or other to block a downstream effect of one of those signalling molecules.

Will modifying the alphabet soup, without providing normoglycaemia, help anything? Well, yes, it will help generate funding.

Prevent AD?

Hahahahahahahaha.

This whole train of thought began with an email from karl linking to this is the editorial:

I've not read the text but the editorial is pretty clear about what they did. Does blockade of lactate dehydrogenase reduce seizures? Yes. But my suspicion is only if the astrocytes/glial cells are being driven hard through glycolysis either in tissue culture (at the "normal" high glucose levels used) or in mice fed crapinabag.

Summary: Lactate dehydrogenase feeds lactate from glial cells to neurons. This is Good. Blocking LDH will control seizures if they are being triggered by over supply of hyperglycaemia derived lactate from astrocytes. Metformin might do the same through all of the Protons logical reasons, ie it delays/limits insulin signalling until fatty acid oxidation replaces the glycerophosphate shuttle. By which time there will be increased beta oxidation leading to glial cell ketone generation... So, metformin SHOULD limit seizures if it promotes glial cell beta oxidation to ketones and reduces excess lactate by limiting insulin signalling. That metformin lowers blood glucose would help too.

rq and Betsy, metformin is interesting because it tells us very critical things about the interaction of the redox state of the cytoplasm and the state of the electron transport chain. It’s effect on diabetes is pathetic compared to a genuine LC diet and I would expect a similarly limited effect on seizures. Berberine would need to be telling us interesting things about the front end of the electron transport chain and how this modifies insulin signalling before I would get too excited about it. Berberine for diabetes looks like a very low efficacy tool compared to ketogenic eating, just looking at the improvements cited in Betsy’s paper. Plus it lowers cholesterol. Falling cholesterol as a very gloomy prognostic marker to me…

Jasmin and Elsa, I can see a role for metformin for people who are struggling with LC. But food first… Also, as Betsy pointed out, met is far from problem free, though not awful as drugs go.

I guess someone needs to convince me that taking an antibiotic like Metformin is worth it. http://www.cysonline.org/article.asp?issn=2229-5186;year=2011;volume=2;issue=4;spage=219;epage=221;aulast=Dash

Metformin use has been a great addition for me. Very interesting blog regarding aed mechanisms of metformin. It enhanced peripheral ketosis without question, I am sure same is true brain. Sleep and mood improved shortly after.

Wooo, when I get round to it I have this idea that metformin is not an antibiotic, it is a drug which blocks the equivalent of mtG3Pdh in bacteria. It will probably also block the equivalent of insulin signalling in bacteria and put those bacteria in to survival mode to deal with this pseudo starvation. One feature of hungry bacteria is FIAF production and liberation of the percentage of adipose tissue owner by those bacteria. This would make a lot of sense to me. Antibiotics at therapeutic dose rates per se cause weight gain because the few surviving bacteria (hard to eliminate all of them) are living in a sea of plenty and FIAF is not going to be on their agenda. Complete elimination of bacteria will set us up as if we were gnotobiotic organisms with their limited fat reserves because there is no trigger for insulin resistance, which looks to be closely tied to bacterial endotoxin absorption and is another way that bacteria store their energy reserves in our adipocytes.... These are the ways I'm thinking at the moment and there is some support out there.

This part of you last comment, Peter, "insulin resistance, which looks to be closely tied to bacterial endotoxin absorption" brought to mind that for the bacterial endotoxins to enter a cell, calcium must first enter. It made me wonder if calcium had anything to do with insulin resistance and I found this.

Preventing β-cell loss and diabetes with calcium channel blockers.

I realize this is a tangent, but I thought someone might be able to expand on it for me.

About Me

I am Petro Dobromylskyj, always known as Peter. I'm a vet, trained at the RVC, London University. I was fortunate enough to intercalate a BSc degree in physiology in to my veterinary degree. I was even more fortunate to study under Patrick Wall at UCH, who set me on course to become a veterinary anaesthetist, mostly working on acute pain control. That led to the Certificate then Diploma in Veterinary Anaesthesia and enough publications to allow me to enter the European College of Veterinary Anaesthesia and Analgesia as a de facto founding member. Anaesthesia teaches you a lot. Basic science is combined with the occasional need to act rapidly. Wrong decisions can reward you with catastrophe in seconds. Thinking is mandatory.
I stumbled on to nutrition completely by accident. Once you have been taught to think, it's hard to stop. I think about lots of things. These are some of them.

Organisation (or lack of it)!

The "labels" function on this blog has been used to function as an index and I've tended to group similar subjects together by using labels starting with identical text. If they're numbered within a similar label, start with (1). The archive is predominantly to show the posts I've put up in the last month, if people want to keep track of recent goings on. I might change it to the previous week if I ever get to time to put up enough posts in a week to justify it. That seems to be the best I can do within the limits of this blogging software!